Antiretrovirals, Doses and Formulations for Children

Both the 5th paediatric workshop and the 7th IAS conference had excellent presentations on pipeline antiretrovirals, dosing strategies and formulations.

Some of the studies made an appearance at both meetings -- as oral or poster presentations -- as co-submission was encouraged. The IAS session "Expanding ARV options for children: first line and beyond" was webcast.1

Atazanavir is currently approved for children aged 6 years and above. PRINCE 1 is an ongoing phase 3b prospective, international, multicentre, open label, two-stage clinical trial -- 48-week data were presented. This trial has been ongoing since 2010

The study enrolled ART-naive or -experienced (without prior ATV use) children with viral load >1000 copies/mL. There were two dosing regimens: stage 1 -- ATV powder boosted with RTV liquid, based on 3 weight bands (see dosing table 1) and stage 2 -- switch to ATV capsules after 48 weeks on ATV powder or when they reached 6 years or >25 kg. Stage 1 efficacy and safety were presented.

Weight (kg)

ATV dose (mg)

RTV dose (mg)

5 to <10

150

80

10 to <15

200

80

15 to <25

250

80

A total of 56 children were enrolled, 46 completed stage 1, and 45 made the transition to stage 2. The majority (68%) of children were from Africa. At baseline, they were a median age of 28.5 months (range 3 to 65), with mean viral load and CD4 counts of 4.62 log10 copies/mL and 1192.6 cells/mm3; 61% were ART-naive.

Using modified intent-to-treat analysis, at week 48, 33 (61%) children had viral load <50 copies/mL, and 40 (74%) had viral load <400 copies/mL. Viral suppression increased with higher weight: 48% in the 5 to <10 kg compared to 71% in the 15 to < 25kg weight band had viral load <50 copies/mL.

There was no significant difference between ART-experienced and -naive children in rate of viral suppression, with 60% and 62% <50 copies/mL respectively. Mean CD4 count change from baseline was 397 cells/mm3, respectively 550, 225 and 374 cells/mm3 in the increasing weight bands.

By week 48, 14 children had virological failure, 57% were ART-naive and 43% ART-experienced. Nine had paired genotypic data (baseline and on treatment) and 6 paired phenotypic. This showed no acquired phenotypic resistance to ATV, ATV/RTV or any NRTI or NNRTI. One child developed phenotypic resistance to saquinavir. No child developed any major PI substitution to ATV or ATV/RTV.

There were no new or unexpected safety events and no deaths. Eleven children (20%) had on treatment SAEs. Five children (9%) discontinued due to AEs, 4 were in the 5 to <10 kg group. Seven (13%) had hyperbilirubinaemia-related AEs and 3 cardiac disorders, 2 were considered related to the study treatment.

Through 48 weeks on ATV powder, common AEs occurred in 52 children (93%); the most frequent being upper respiratory tract infections (36%), diarrhea (36%) and vomiting (29%).

The PRINCE 2 study of ATV powder in 3 months to <11 in 95 children years is ongoing. A PK, safety and efficacy analysis of the combined data sets will be conducted.

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Darunavir

Darunavir/ritonavir (DRV/r) plus an optimised background regimen was effective in treatment-experienced children, with no new safety concerns compared to adults at 48-weeks in the ARIEL trial.4

The primary 24-week analysis from this phase 2, multicentre, international trial led to the approval of DRV/r for treatment experienced children aged 3 to <6 weighing at least 10 kg.

Children enrolled in ARIEL had been on ART for 12 weeks or more with viral load >1000 copies/mL and less than three darunavir-associated mutations.

They initially received DRV oral suspension at 100mg/mL plus RTV 20/3mg/kg twice daily with an optimised background regimen. Following pharmacokinetic (PK) analysis after two weeks of receiving this dosing regimen and Data and Safety Monitoring Board recommendations, children weighing <15 kg and 15 to < 20kg were given DRV/r 25/3mg/kg and 375/50mg twice-daily respectively.

The 48-week analysis included 21 children with a median age of 4.4 years (range 3-6) at enrollment. Their mean baseline viral load was 4.34 copies/mL, median CD4 count 927 cells/mm3 and CD4 percentage 27.7%.

The majority of the children received two background NRTIs and two children received three NRTIs.

At week 48, 81.0% of children had viral load <50 copies/mL and 85.7% <400 copies/mL (ITT-TLOVR). Notably at 24 weeks only 57.1% of children had achieved virological suppression <50 copies/mL but 81.0% were <400 copies/mL.

Two children with baseline DRV mutations (L33FL and L76V) had viral load <50 copies/mL at 24 and 48 weeks. There were 3 virologic failures at week 48 (2 never suppressed; 1 rebounder); of the 2 with paired baseline/endpoint genotypes, neither developed PI nor NRTI mutations. Both remained susceptible to DRV and other NRTIs in the background regimen.

There was one AE possibly related to DRV (ECG QT prolongation), and one discontinuation due to grade 2 vomiting probably related to RTV. Two children had grade 4 AEs (stenosing tenosynovitis and asthmatic crisis), both considered serious but not related to the study treatment. All laboratory abnormalities were grade 1 except for one grade 3 neutropenia, which had been present at baseline and was not considered treatment-related.

A small Thai pilot study looked at PK and efficacy of once daily compared to twice daily dosing of DRV/r in older children and adolescents.5

Treatment-experienced children and adolescents receiving DRV/r twice daily in optimised regimens, with no prior DRV-associated mutations, and virologically suppressed (<400 copies/mL) for at least 6 months were enrolled.

Twelve-hour blood sampling (pre-dose and 2, 4, 6, 8 and 12 hours post-dose) for PK was performed at enrollment. DRV/r was then switched to once daily dosing and 24 hour sampling (as previously but with 18 and 24 hours post dose) was repeated 2 weeks later. Twice daily DRV/r doses of 375/100, 450/100, and 600/100 mg were increased to once daily doses of 450/100, 600/100, and 900/100 mg, respectively.

DRV/r PK parameters were calculated using non-compartmental analysis. CD4 counts and viral load were measured at baseline and at 12, 24, 36 and 48 weeks.

Eight children and adolescents with a median age of 16 years (range 11.0-18.9) were evaluated. Their median CD4 count was 806 cells/mm3 (range 621-1200). DRV AUC0-24h with twice daily and once daily dosing was 59.6 (range 38.5-139.3) and 51.5 (range 20.7-117.7) mcg.hr/mL, respectively. The C12h and C24h DRV concentrations were 1.4 (range 0.7-4.9) and 0.7 (range 0.2-2.4) mg/L, respectively.

This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

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